Chymase is a neutral protease present in mast cell granules, and is intimately involved in various biological reactions participated in by mast cells. For example, chymase has been reported to have various actions, including the promotion of degranulation from mast cells, activation of Interleukin-1β (IL-1β), activation of matrix protease, decomposition of fibronectin and type IV collagen, promotion of the liberation of transforming growth factor-β (TGF-β), activation of substance P and vasoactive intestinal polypeptide (VIP), conversion from angiotensin I (Ang I) to angiotensin II (Ang II), and conversion of endothelin.
On the basis of the above, inhibitors of said chymase activity are considered to be promising as preventive and/or therapeutic agents against respiratory diseases such as bronchial asthma, inflammatory and allergic diseases such as allergic rhinitis, atopic dermatitis and urticaria, cardiovascular diseases such as sclerosing vascular lesions, vasoconstriction, peripheral circulatory disorders, renal insufficiency and cardiac insufficiency, and bone and cartilage metabolic diseases such as rheumatoid arthritis and osteoarthritis.
Although known examples of chymase activity inhibitors of the prior art include a triazine derivative (Japanese Unexamined Patent Publication No. 8-208654), hydantoin derivative (Japanese Unexamined Patent Publication No. 9-31061), imidazolidine derivative (International Publication No. WO96/04248), quinazoline derivative (International Publication No. WO97/11941), heterocyclic amide derivative (International Patent Publication No. WO96/33974), cefam compound (Japanese Unexamined Patent Publication No. 10-087493), phenol derivative (Japanese Unexamined Publication No. 10-087567), heterocyclic amide compound (International Publication No. WO98/18794), acetoamide derivative (International Publication No. WO98/09949), heterocyclic amide compound (Japanese Unexamined Publication No. 10-007661), acid anhydride derivative (Japanese Unexamined Patent Publication No. 11-049739), heterocyclic amide compound (International Publication No. WO99/32459) and acetoamide derivative (International Publication No. WO99/41277), these compounds and the compound of the present invention are completely different structurally.
The chymase inhibitor compounds disclosed thus far have lacked usefulness as a result of having inadequate activity or being structurally unstable. However, the compound of the present invention has extremely high activity and demonstrates superior kinetics in the blood, making it highly useful as a drug.
On the other hand, an example of a technology related to the compound of the present invention is described in the specification of U.S. Pat. No. 5,124,336. A benzimidazole derivative is described in said specification as a compound that has thromboxane receptor antagonistic activity. However, the compound described in said specification is not disclosed as having a heteroaryl group substituted in the benzimidazole skeleton, and there is also no description of human chymase activity of said compound. In addition, although a benzimidazole compound is also described as an antitumor agent in Japanese Unexamined Patent Publication No. 01-265089, there is no mention of human chymase inhibitory activity.